ORIGINAL RESEARCH

Similar Pharmacokinetics of the Adalimumab(Humira�) BiosimilarBI 695501WhetherAdministeredvia Subcutaneous Autoinjector or Prefilled Syringe(VOLTAIRE�-AI and VOLTAIRE�-TAI): Phase 1,Randomized, Open-Label, Parallel-Group Trials

Steven Ramael . Benjamin Van Hoorick . Renger Tiessen . Thijs van Iersel . Viktoria Moschetti .

Benjamin Lang . Ivo Sonderegger . Sabrina Wiebe . Bernd Liedert . Girish Jayadeva

Received: April 19, 2018 / Published online: June 29, 2018� The Author(s) 2018

ABSTRACT

Introduction: BI 695501 has shown similarefficacy, safety, and immunogenicity to theadalimumab reference product, Humira�. Wepresent two phase 1 studies comparing thepharmacokinetics, safety, and immunogenicityof BI 695501 delivered via autoinjector (AI) vs.prefilled syringe (PFS).Methods: Both trials were randomized, open-label, parallel-group studies undertaken in

subjects aged C 18–65 years. VOLTAIRE�-AI(NCT02606903) recruited healthy, Caucasian,male, non-athletic volunteers with BMI C 18to B 30 kg/m2. VOLTAIRE�-TAI (NCT02899338)recruited healthy men and women withBMI[17.5 to\35 kg/m2. Inboth studies, a singledoseofBI69550140mgwasadministeredviaAIorPFS to the abdomen (VOLTAIRE�-AI) or thigh(VOLTAIRE�-TAI). The observation period was43/57 days and the safety follow-up was 70 days.Co-primary endpoints were AUC0–1032 orAUC0–1368, Cmax, and AUC0–?. Safety andimmunogenicity were assessed.Results: Subjects (VOLTAIRE�-AI: N = 71;VOLTAIRE�-TAI: N = 162) were randomized toAI (n = 35; n = 81) or PFS (n = 36; n = 81).Baseline characteristics were balanced betweentreatment groups in each study. Total exposureof BI 695501 was similar for both groups;adjusted geometric mean ratios for AUC0–?,AUC0–1032, and Cmax were 106.17, 104.09, and114.83%, respectively, for VOLTAIRE�-AI;103.19, 101.71 (AUC0–1368), and 100.11% forVOLTAIRE�-TAI. In both studies, similarimmunogenicity was observed between groupsin terms of frequency of binding and neutral-izing anti-drug antibody-positive subjects. Inci-dence of adverse events was similar for bothgroups.Conclusions: Pharmacokinetics and immuno-genicity of BI 695501 delivered via AI weresimilar to administration using a PFS, indepen-dent of injection site. No differences are

Steven Ramael and Benjamin Van Hoorick: Co-primaryauthors.

Enhanced digital features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.6456035.

Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s40744-018-0119-1) contains supplementary material, which isavailable to authorized users.

S. Ramael (&) � B. Van HoorickSGS Life Science Services, CPU, Antwerp, Belgiume-mail: steven.ramael@sgs.com

R. Tiessen � T. van IerselPRA Health Sciences, Groningen, The Netherlands

V. Moschetti � I. Sonderegger � B. Liedert �G. JayadevaBoehringer Ingelheim, Ingelheim am Rhein,Germany

B. Lang � S. WiebeBoehringer Ingelheim, Biberach, Germany

Rheumatol Ther (2018) 5:403–421

https://doi.org/10.1007/s40744-018-0119-1

expected between AI and PFS use in clinicalpractice.Funding: Boehringer Ingelheim.

Keywords: Adalimumab; Autoinjector; Biosim-ilar; BI 695501; Prefilled syringe

INTRODUCTION

Adalimumab is a recombinant human mon-oclonal antibody that binds specifically totumor necrosis factor (TNF)a and neutralizesits biological function by blocking its inter-action with TNFa receptors 1 and 2 [1]. It isan efficacious treatment for several autoim-mune and inflammatory disease conditions,including rheumatoid arthritis (RA), psoria-sis, Crohn’s disease, ulcerative colitis,hidradenitis suppurativa, and non-infectiousuveitis [1].

BI 695501 is a biosimilar to Humira� [2, 3].BI 695501 was demonstrated to be structurallyand functionally highly similar to Humira�

(data on file). In a three-way comparativepharmacokinetic (PK) trial (VOLTAIRE�-PK)conducted in healthy subjects, bioequivalence(BE) was established between BI 695501, US-,and EU-approved Humira� [4]. Similarity ofefficacy, safety, and immunogenicity betweenBI 695501 and Humira� was demonstrated inthe VOLTAIRE�-RA study [5].

Adalimumab is administered via subcuta-neous (SC) injection to either the abdomen orthe thigh [1]. Drugs that require regular SCadministration can be administered via prefilledsyringe (PFS) or, via autoinjector (AI). Selectionof the appropriate presentation should be basedon individual patient (or carer) characteristicsand preferences [6]. AIs have demonstratedimproved comparative usability over PFSs inpatients with severe RA, in terms of pain expe-rienced, ease of use, and convenience, withsimilar tolerability [6]. These factors are ofconsiderable importance, especially whenmanual dexterity is compromised, for example,when RA causes pain in the fingers or damagesfinger joints [7].

US FDA guidance [8] states that approval ofan AI presentation requires a PK bridging study

to demonstrate similar PK profiles across a rangeof body weights, alongside human factor studiesand real-life patient handling experience. Theaim of the VOLTAIRE�-AI and VOLTAIRE�-TAIstudies was to assess the relative bioavailabilityof BI 695501 administered via AI vs. PFS across abroad range of body mass index (BMI) and bodyweights, with two different administrationlocations. Safety, tolerability, and immuno-genicity were also assessed.

METHODS

Study Designs

VOLTAIRE�-AI (NCT02606903)This randomized, single-dose, parallel-arm,open-label, phase 1 trial of BI 695501, deliveredvia AI or PFS in the abdomen, was conducted ata single site in Belgium between October 29,2015 and October 4, 2016. An initial screeningperiod of up to 28 days was followed by a single-dose administration of BI 695501 via AI or PFS.After drug administration, there was a 43-dayobservation period and a safety follow-up per-iod of up to 70 days.

VOLTAIRE�-TAI (NCT02899338)This randomized, single-dose, parallel-arm,open-label, phase 1 trial of BI 695501, deliveredvia AI or PFS in the thigh, was conducted at twosites: one in Belgium and one in the Nether-lands. The date of first enrollment wasSeptember 22, 2016; the last subject completedon February 23, 2017. An initial screening per-iod of up to 28 days was followed by a single-dose administration of BI 695501 via AI or PFS.After drug administration, there was a 57-dayobservation period and a safety follow-up per-iod of up to 70 days.

Both studies were approved by independentethics committees and the competent authori-ties, and conducted in accordance with theInternational Council for Harmonisation ofTechnical Requirements for Pharmaceuticals forHuman Use Good Clinical Practice (GCP)guidelines and the Declaration of Helsinki [9].All subjects provided written, informed consentprior to participation.

404 Rheumatol Ther (2018) 5:403–421

Study Populations

VOLTAIRE�-AIThe study enrolled healthy, non-athletic, adult,Caucasian males aged 18–65 years with a BMI of18–30 kg/m2. Exclusion criteria included priorexposure to a biologic, or exposure to drugswith a half-life (t1/2)[24 h, within 30 daysor\5 half-lives prior to administration of trialmedication.

VOLTAIRE�-TAIThe study enrolled healthy male and femalevolunteers aged 18–65 years with a BMI of17.5–35 kg/m2. Subjects were excluded if theyhad any prior exposure to adalimumab, or druguse within 10 days prior to administration thatmight affect the results of the study.

The tissue into which a drug is injected canaffect PK, and this in turn can be influenced bythe amount of SC fat. As the quantity of SC fattissue correlates with body weight and BMI [10],randomization in VOLTAIRE�-AI was stratifiedby BMI category (18.0–\20.0; 20.0–\25.0,25.0–B 30.0 kg/m2) and in VOLTAIRE�-TAI bybody weight categories (low: B 60.0 kg,medium:[60.0–\90.0 kg, and high: C 90.0 kg).The trial populations therefore covered a broadrange of subjects with respect to BMI and bodyweight.

Detailed inclusion and exclusion criteria forboth trials are provided in the supplementaldigital content.

Interventions

VOLTAIRE�-AISubjects were randomized 1:1 to receive a singleSC administration of BI 695501 40 mg/0.8 ml,via either AI or PFS (Fig. 1). Injections were tothe lower abdomen with the subjects in asupine position. Subjects were placed underclose, residential supervision for the first 24 hfollowing drug administration.

VOLTAIRE�-TAISubjects were randomized 1:1 to receive a singleSC administration of BI 695501 40 mg/0.8 ml,

via either AI or PFS. Injections were to the frontof the thigh.

For both studies, the spring-powered AI(Fig. 1a) and the standard PFS (Fig. 1b) includeda 1-ml syringe. Details of the injection processesare presented in the supplemental digitalcontent.

The BI 695501 40-mg/0.8-ml dose wasdeemed to have an acceptable risk/benefit ratioin healthy subjects and reflected the standardclinical dose.

Study Endpoints

VOLTAIRE�-AIThree co-primary endpoints were investigatedfor BI 695501: area under the plasma concen-tration–time curve (AUC) from 0 to 1032 h post-dose (AUC0–1032); maximum plasma concen-tration (Cmax); and AUC from 0 extrapolated toinfinity (AUC0–?), based on observed concen-trations at the last observation.

VOLTAIRE�-TAIThree co-primary endpoints were investigatedfor BI 695501: AUC from 0 to 1368 h post-dose(AUC0–1368); Cmax; and AUC0–?, based onobserved concentrations at the last observation.

In both studies, the secondary endpoint wasthe number of subjects with drug-related treat-ment-emergent adverse events (AEs) occurringfrom day 1 to day 70. Additional PK, safety, andimmunogenicity parameters were also assessed.

PK Methodology and ImmunogenicityAssays

Blood samples for PK analyses were drawn dailyon days 0–8, and then on days 10, 15, 22, 29, 36,and 43 (and at day 57 in VOLTAIRE�-TAI) afteran overnight (at least 10-h) fast. BI 695501plasma concentration was determined via avalidated enzyme-linked immunosorbent assay,as described by Wynne et al. 2016. Blood sam-ples for immunogenicity analyses were drawn atbaseline (pre-dose) and throughout the studies[days 22 and 43 (VOLTAIRE�-AI); days 22 and57 (VOLTAIRE�-TAI)]. Anti-drug antibodies(ADA) and neutralizing antibodies (nAb)

Rheumatol Ther (2018) 5:403–421 405

measurements were performed with validatedassays [a single bridging electrochemilumines-cence assay on the MSD platform (Meso ScaleDiagnostics LLC, Rockville, MA, USA) for ADAmeasurements, and a cell-based, antibody-de-pendent cell-mediated cytotoxicity method fornAb measurements], as described by Wynneet al. 2016 [4].

Statistical Analyses

In agreement with regulatory advice at thetime of study design, the sample size forVOLTAIRE�-AI was set at 66 subjects to com-pare the bioavailability of BI 695501 admin-istered by AI and PFS with sufficient precision.For VOLTAIRE�-TAI, it was planned to enter atotal of 160 subjects for the primary bioavail-ability comparison. Updated regulatoryrequirements in comparison to VOLTAIRE�-AIrequired higher precision for estimation ofeffects, thus, the higher sample size wasselected for VOLTAIRE�-TAI to assess the pri-mary objective. The sample size calculationswere performed with nQuery Version 2.0.1.0(Statistical Solutions Ltd, Cork, Ireland).

All PK analyses were conducted using the PKanalysis set, which included all subjects whoreceived the single dose of study medication,had C 1 evaluable primary PK endpoint, andhad no protocol deviations considered relevantto affect PK assessments.

Safety and immunogenicity evaluations wereconducted on the safety analysis set, consistingof all subjects who received the single dose ofstudy medication.

Exploratory analyses were performed toestimate the relative bioavailability ofBI 695501 administered via AI compared withPFS, using an analysis of variance (ANOVA)model of the logarithmically transformed pri-mary PK parameters (Cmax, AUC0–?, andAUC0–1032/AUC0–1368), with fixed effects fortreatment and BMI group (VOLTAIRE�-AI) orbody weight (VOLTAIRE�-TAI). Point estimatesof relative bioavailability for PK parameters andtheir two-sided 90% confidence intervals (CIs)were calculated [ratio of geometric means(gMean); AI vs. PFS]. In VOLTAIRE�-AI, anadditional sensitivity analysis was conductedto estimate the primary PK endpoints forBI 695501 using an analysis of covariance(ANCOVA) model on a logarithmic scale, with afixed effect for treatment and baseline BMI as acontinuous covariate.

CIs were compared using the standard BEacceptance range, even though no formal BEtesting was required.

Scatterplots and boxplots were used tographically evaluate Cmax, AUC0–?, andAUC0–1032 (AUC0–1368 for VOLTAIRE�-TAI) forAI vs. PFS administration.

Descriptive statistics were provided for addi-tional PK parameters, safety, tolerability, andimmunogenicity.

Plunger rod

Grip

Plunger

Injection button

(b)(a)

Grip

Medication

Window

Cap

Tip (needle guard)

Plunger (inside)

Medication

Needle

Cap

Fig. 1 a AI and b PFS presentations. AI autoinjector, PFS prefilled syringe

406 Rheumatol Ther (2018) 5:403–421

RESULTS

Subject Demographics and BaselineCharacteristics

VOLTAIRE�-AIA total of 122 subjects were screened and initially66 were randomized (original population data set;Fig. 2a). Due to lower-than-required recruitmentin the lowest BMI group (\20 kg/m2), an addi-tional five subjects were enrolled (full populationdata set). All data presented here are from this fullpopulation data set (N = 71; 35 to AI and 36 toPFS), other than for the primary endpoint analy-sis, for which the original analysis plan (N = 66)was retained per protocol. All subjects completedthe trial (Fig. 2a).

VOLTAIRE�-TAIA total of 362 subjects were screened, and 162were randomized to AI (n = 81) or PFS (n = 81)(Fig. 2b). One hundred and fifty-seven subjectscompleted the trial per protocol; two out of fivewho were prematurely discontinued werereplaced.

In both studies, demographics and baselinecharacteristics were balanced between treat-ment groups (Table 1).

Pharmacokinetics—Co-primary Endpoints

VOLTAIRE�-AIAssessment of relative bioavailability ofBI 695501 administered via either AI or PFSshowed that the total exposure of BI 695501 for

Screened (n = 362)

Randomized (n = 162)

Screen failure (n = 200)

BI 695501 AI (n = 81)

Completed follow-up (n = 80)*

Completed EOT visit (n = 79)

BI 695501 PFS (n = 81)

Completed follow-up (n = 78)

Completed EOT visit (n = 78)

(b)

Screened (n = 122)

Randomized (n = 71)

Screen failure (n = 51)

Completed follow-up (n = 35)

Completed EOT visit (n = 35)

BI 695501 PFS (n = 36)

Completed follow-up (n = 36)

Completed EOT visit (n = 36)

BI 695501 AI (n = 35)

(a)

Discontinued (n = 2) Discontinued (n = 3)

Fig. 2 Patient disposition in a VOLTAIRE�-AI and b VOLTAIRE�-TAI. AI autoinjector, EOT end of trial, PFS prefilledsyringe. *Patients who did not complete the EOT visit could still complete the day 70 safety follow-up visit

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the two treatment groups was similar (Table 2a).Adjusted gMean ratios for AUC0–? andAUC0–1032 fell within the BE acceptance range80–125%. The upper 90% CI limit for AUC0–?

was 130.56%, slightly above the upper BEacceptance limit of 125%, while the 90% CI forAUC0–1032 (123.39%) was contained within thestandard acceptance range of BE. The adjustedgMean ratio point estimate for Cmax ofBI 695501 administered via AI compared withPFS (114.83%) was within the standard BEacceptance range, while the upper 90% CI limit(130.75%) was again slightly above the upper BEacceptance limit. The primary analysis for the

full population data set (N = 71) is shown inTable 2b. The 90% CI limits for AUC0–?,AUC0–1032, and Cmax were all within the BEacceptance range of 80–125%, except for theupper 90% CI limit for Cmax (125.44%).

Primary PK parameters were also estimatedtreating baseline BMI as a continuous covariate(rather than as a categorical variable). In thisanalysis, gMean ratio point estimates of thethree primary PK parameters were lower com-pared with the primary analysis and 90% CIswere all entirely within the 80–125% standardBE acceptance range (Table 3).

Table 1 Demographics and baseline characteristics

Parameter (unit) VOLTAIRE�-AI VOLTAIRE�-TAI

AI (N = 35) PFS (N = 36) AI (N = 81) PFS (N = 81)

Age, years (SD) 39.3 (13.8) 40.1 (13.3) 41.5 (14.4) 44.5 (14.7)

Gender, n (%)

Male 35 (100) 36 (100) 38 (46.9) 37 (45.7)

Female 0 0 43 (53.1) 44 (54.3)

Race, n (%)

Asian 0 0 2 (2.5) 0

Black/African American 0 0 1 (1.2) 3 (3.7)

White 35 (100) 36 (100) 77 (95.1) 78 (96.3)

Other 0 0 1 (1.2) 0

Mean BMI, kg/m2 (SD) 24.1 (3.0) 24.2 (3.2) 25.5 (3.7) 25.1 (3.9)

BMI category, n (%)

C 18–\ 20 kg/m2 5 (14.3) 6 (16.7) – –

C 20–\ 25 kg/m2 15 (42.9) 15 (41.7) – –

C 25–\ 30 kg/m2 15 (42.9) 15 (41.7) – –

Mean weight, kg (SD) 78.3 (9.3) 79.2 (12.4) 75.3 (14.9) 74.8 (15.4)

Median weight, kg (min; max) 77.0 (62.0; 104.0) 80.9 (54.2; 109.2) 73.5 (49.2; 113.8) 73.2 (48.4; 116.0)

Body weight category, n (%)

B 60 kg – – 15 (18.5) 14 (17.3)

[ 60–\ 90 kg – – 52 (64.2) 52 (64.2)

C 90 kg – – 14 (17.3) 15 (18.5)

AI autoinjector, BMI body mass index, PFS prefilled syringe, SD standard deviation

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Pharmacokinetics—Further Assessments

For the overall population, mean plasma con-centration–time profiles for BI 695501 admin-istered via AI and via PFS were similar over theentire observation period (Fig. 3a). On average,concentrations of BI 695501 rose relativelyrapidly over the first 48–60 h and continued torise gradually until a median tmax of approxi-mately 4.5–5.5 days (108–132 h) (Fig. 3a;

Table 4a). Afterwards, concentrations declinedslowly and were still measurable for most sub-jects at the final sampling time point.

Variability in primary PK parameters wasmoderate to high [geometric coefficient of varia-tion (gCV): 27.4–58.2%; Table 4a]. Two subjectshad unexpected PK profiles: one person in the PFSgroup had particularly low exposure to BI 695501,not reflective of levels generally seen in this study;a second subject, also in the PFS group, had a

Table 2 Primary analysis of PK parameters for BI 695501 administered via either AI or PFS: (a) VOLTAIRE�-AI originalanalysis plan, N = 66; (b) VOLTAIRE�-AI full population data set, N = 71; (c) VOLTAIRE�-TAI

VOLTAIRE�-AIparameter

BI 695501 AI BI 695501 PFS Adj-gMean ratio(AI/PFS), %

Two-sided 90% CI Inter-individualgCV, %

N Adjusteda

gMeanN Adjusteda

gMeanLowerlimit, %

Upperlimit, %

(a)

AUC0–?

(lg h/ml)b33 2320 32c 2180 106.17 86.34 130.56 53.16

AUC0–1032

(lg h/ml)

33 1960 32c 1890 104.09 87.81 123.39 42.83

Cmax (lg/ml) 33 4.07 33 3.54 114.83 100.86 130.75 32.37

(b)

AUC0–?

(lg h/ml)b35 2280 35c 2270 100.22 82.13 122.29 53.14

AUC0–1032

(lg h/ml)

35 1960 35c 1960 100.14 85.15 117.76 42.35

Cmax (lg/ml) 35 4.14 36 3.76 110.19 96.80 125.44 33.60

(c)

AUC0–?

(lg h/ml)b79 2320 76 2250 103.19 91.38 116.53 48.21

AUC0–1368

(lg h/ml)

79 2140 76 2110 101.71 91.31 113.29 42.28

Cmax (lg/ml) 81 3.86 79 3.86 100.11 94.17 106.43 23.72

Adj adjusted, AI autoinjector, AUC0–? area under the plasma concentration–time curve from 0 extrapolated to infinity,AUC0–1032 area under the plasma concentration–time curve from 0 to 1032 h post-dose, AUC0–1368 area under the plasmaconcentration–time curve from 0 to 1368 h post-dose, BMI body mass index, CI confidence interval, Cmax maximumplasma concentration, gCV geometric coefficient of variation, gMean geometric mean, PFS prefilled syringe, PKpharmacokineticsa Adjusted for treatment and BMI group (a and b) or treatment and baseline body weight (c) as fixed effectsb Based on observed last concentration valuesc AUC values could not be calculated for one subject due to the lack of appropriate terminal phase

Rheumatol Ther (2018) 5:403–421 409

profile indicative of accidental intravenous ratherthan SC injection. In a post hoc sensitivity anal-ysis (Table 5) that excluded these two subjects,the adjusted gMean ratio for Cmax decreased from110.19% to 108.47% and the 90% CI(97.86–120.22%) fell within the standard80–125% range. For the first subject, AUC calcu-lations could not be performed due to the lack ofa real terminal phase; exclusion of the secondsubject caused a slight increase in the adjustedgMean ratio for AUC0–? (100.22–102.76%) andAUC0–1032 (100.14–102.01%).

Pharmacokinetics in BMI Groups

As a secondary analysis of the primary PK end-points, relative bioavailability was evaluatedwithin each BMI group, to assess the influenceof body fat content on exposure. As expected,the 90% CIs widened, primarily due to a smallernumber of subjects per group. In the low BMIgroup, gMeans were higher with PFS presenta-tion than with AI presentation, whereas in thehigh BMI group, gMeans were higher with AI vs.PFS presentation (see supplemental material).

Scatterplots of AUC0–? and Cmax by BMIcategory (Fig. 4a, b) show a slight inverse cor-relation between BMI and exposure, which wassimilar regardless of presentation.

VOLTAIRE�-TAIAssessment of relative bioavailability ofBI 695501 administered via either AI or PFSshowed that the total exposure of BI 695501 forthe two administration methods was similar(Table 2c). Adjusted gMean ratios were 103.19%for AUC0–?, 101.71% for AUC0–1368, and100.11% for Cmax. All 90% CIs for the primaryendpoints were within the standard BE accep-tance range of 80–125%.

Pharmacokinetics—Further Assessments

Mean plasma concentration–time profiles forBI 695501 administered via AI and via PFS weresimilar over the entire observation period(Fig. 3b). Concentrations of BI 695501 roserapidly over the first 48–60 h and continued torise gradually until a median tmax of approxi-mately 6–7 days (144–168 h) (Fig. 3b; Table 4b).Thereafter, concentrations declined slowly andwere still measurable for approximately 60% ofsubjects at the final sampling time point.

gMean PK parameters from the overall trialpopulation for BI 695501 were similar for AI andPFS (Table 4b). A similarly moderate inter-indi-vidual variability was observed for both pre-sentations (gCV: 23.6–50.4%).

Table 3 Sensitivity analyses of PK parameters over all BMI levels (baseline BMI as a continuous covariate rather thancategorical variable) for BI 695501 administered via AI or PFS in VOLTAIRE�-AI

VOLTAIRE�-AIparameter

BI 695501 AI BI 695501 PFS Adj-gMean ratio(AI/PFS), %

Two-sided 90% CI Inter-individualgCV, %

N Adjusteda

gMeanN Adjusteda

gMeanLowerlimit, %

Upperlimit, %

AUC0–?

(lg h/ml)b35 2070 35c 2110 98.36 80.37 120.37 54.08

AUC0–1032

(lg h/ml)

35 1810 35c 1840 98.48 83.50 116.15 43.23

Cmax (lg/ml) 35 3.78 36 3.49 108.26 95.24 123.05 33.22

Adj adjusted, AI autoinjector, AUC0–? area under the plasma concentration–time curve from 0 extrapolated to infinity,AUC0–1032 area under the plasma concentration–time curve from 0 to 1032 h post-dose, BMI body mass index, CIconfidence interval, Cmax maximum plasma concentration, gCV geometric coefficient of variation, gMean geometric mean,PFS prefilled syringe, PK pharmacokineticsa Adjusted for treatment and continuous BMI as fixed effectsb Based on observed last concentration valuesc AUC values could not be calculated for one subject due to the lack of appropriate terminal phase

410 Rheumatol Ther (2018) 5:403–421

Pharmacokinetics by Body Weight

In scatterplots (Fig. 4c, d), the individual expo-sure values (AUC0–?, AUC0–1368, and Cmax)overlapped for the AI and the PFS groups. Therelationship between exposure and baselinebody weight, particularly for Cmax, appeared tobe similar for both treatment groups.

Safety

VOLTAIRE�-AIIn the AI and PFS groups, 29 (82.9%) and 29(80.6%) of subjects reported C 1 AE, respec-tively (Table 6). AEs reported in[ 5% of sub-jects are shown in Table 7. No serious AEs werereported. One AE of special interest (rash) wasreported by a subject in the PFS group. There

were no AEs leading to discontinuation, ordeaths reported during the trial.

Injection-site reactions (ISRs) were observedin a numerically greater proportion of subjectsin the Al group [20 subjects (57.1%)] comparedwith the PFS group [14 subjects (38.9%)]. Allwere mild in intensity, and resolved withinhours in the majority of subjects, without theneed for corrective treatment.

VOLTAIRE�-TAIIn the AI and PFS groups, 61 (75.3%) and 85(71.6%) of subjects reported C 1 AE, respec-tively (Table 6). One or more drug-related AEswere reported in 31 (38.3%) and 30 (37.0%) ofpatients in the AI and PFS groups, respectively.AEs reported in[ 5% of subjects are shown inTable 7. Three subjects had a serious AE: two

Fig. 3 Arithmetic mean plasma concentration–time profiles for BI 695501 administered via AI or PFS (± SD) ina VOLTAIRE�-AI and b VOLTAIRE�-TAI. AI autoinjector, PFS prefilled syringe, SD standard deviation

Rheumatol Ther (2018) 5:403–421 411

subjects in the AI group (seizure and ligamentrupture) and one subject in the PFS group (wristfracture). None of these were related to trialdrug and all led to discontinuation of the sub-jects. There were no deaths in the trial.

ISRs were observed in a numerically greaterproportion of subjects in the Al group [26 sub-jects (32.1%)] compared with the PFS group [20subjects (24.7%)]. All were non-serious; allexcept one were mild in intensity. The majority

Table 4 Descriptive statistics of PK parameters over all BMI groups for BI 695501 administered via AI or PFS in(a) VOLTAIRE�-AI and (b) VOLTAIRE�-TAI

VOLTAIRE�-AI parameter BI 695501 AI BI 695501 PFS

N gMean gCV, % N gMean gCV, %

(a)

AUC0–? (lg h/ml)a 35 2080 58.2 35b 2110 58.0

%AUCtz-? (%) 35 6.10 383 35b 6.31 296

AUC0–1032 (lg h/ml) 35 1810 47.5 35b 1840 47.1

Cmax (lg/ml) 35 3.79 27.4 36 3.48 51.0

t1/2 (h) 35 205 117 35b 225 97.9

VOLTAIRE�-AI parameter BI 695501 AI BI 695501 PFS

N Median Min; Max N Median Min; Max

tmax (h) 35 108 48.0; 337 36 132 8.00; 336

VOLTAIRE�-TAI parameter BI 695501 AI BI 695501 PFS

N gMean gCV, % N gMean gCV, %

(b)

AUC0–? (lg h/ml)a 79 2330 50.4 76 2250 50.3

%AUCtz-? (%) 79 3.42 299 76 2.70 260

AUC0–1368 (lg h/ml) 79 2150 45.2 76 2100 43.9

Cmax (lg/ml) 81 3.86 23.6 79 3.86 27.8

t1/2 (h) 79 217 112 76 195 95.7

CL/F (ml/min) 79 0.286 50.3 76 0.297 50.3

Vz/F (l) 79 5.37 78.4 76 5.00 63.2

VOLTAIRE�-TAI parameter BI 695501 AI BI 695501 PFS

N Median Min; Max N Median Min; Max

tmax (h) 81 144 48.1; 504 79 168 48.2; 340

AI autoinjector, AUC0–? area under the plasma concentration–time curve from 0 extrapolated to infinity, AUC0–1032 areaunder the plasma concentration–time curve from 0 to 1032 h post-dose, AUC0–1368 area under the plasma concentra-tion–time curve from 0 to 1368 h post-dose, %AUCtz-? percentage of the area under the concentration-time curve fromtime tz to infinity obtained by extrapolation, BMI body mass index, Cmax maximum plasma concentration, gCV geometriccoefficient of variation, gMean geometric mean, PFS prefilled syringe, PK pharmacokineticsa Based on observed last concentration valuesb Values could not be calculated for one subject due to the lack of appropriate terminal phase

412 Rheumatol Ther (2018) 5:403–421

of events resolved within 1 or 2 days, withoutthe need for treatment.

Immunogenicity

In both studies, similar frequencies of ADA-positive subjects, ADA titers, and frequencies ofnAb-positive subjects were observed across AIand PFS groups (Fig. 5). In VOLTAIRE�-AI, byday 43, the median ADA titer in the AI and PFSgroups were 8 and 4, respectively. In VOL-TAIRE�-TAI, by day 57, the median ADA titerwas 8 in both AI and PFS groups. Antibody titersin ADA-positive subjects evolved in a similarway across the two groups (Fig. 6).

DISCUSSION

The primary objective of both VOLTAIRE�-AIand VOLTAIRE�-TAI was to compare the PK ofBI 695501 40 mg administered as a single SCinjection using an AI vs. a PFS, in a broad rangeof BMI and body weights, and in two differentadministration locations. Total and peak expo-sure of BI 695501 for the two administrationmethods was similar regardless of injection site;the AI-to-PFS adjusted gMean ratio point esti-mates for the primary endpoints AUC0–1032,AUC0–?, and Cmax were all within the 80–125%BE acceptance range (both studies).

CIs were compared using the standard BEacceptance range, even though no formal BEtesting was required. All upper and lower CIlimits in VOLTAIRE�-TAI were within the stan-dard acceptance range. In VOLTAIRE�-AI, onlythe upper 90% CI limit for Cmax (125.44%) wasslightly above the standard upper limit of 125%.This is unlikely to be clinically relevant; Pouwet al. [11] have shown that clinical efficacyimproves with increasing adalimumab concen-tration then reaches a plateau at levels between5 and 8 mg/ml. In a post hoc sensitivity analysisof VOLTAIRE�-AI with baseline BMI as a con-tinuous covariate, the resulting upper 90% CIlimit came within the standard 80–125%range (123.05%). These data suggest the PK ofBI 695501 can be considered comparable whe-ther administered via AI or PFS.

Humira� is approved for SC administrationin the abdomen and the thigh, and patients areadvised to rotate their injection sites [1]. Thelocation of injection is thought to play a role indetermining the therapeutic outcomes of SCinjected biopharmaceuticals, based on differ-ences in the physical, chemical, and physio-logical properties of the SC tissue [12]. As such,it was important to evaluate BI 695501 in bothabdomen and thigh injection sites, necessitat-ing the two replicate studies presented here.

Randomization was stratified by BMI cate-gory in VOLTAIRE�-AI, and by body weight

Table 5 Sensitivity analysis of PK parameters for BI 695501 administered via PFS or AI, excluding two subjects inVOLTAIRE�-AI

VOLTAIRE�-AIparameter

AI PFS Adjusteda gMeanratio (AI/PFS), %

Two-sided 90% CI Inter-individualgCV, %

N Adjusteda

gMeanN Adjusteda

gMeanLowerlimit, %

Upperlimit, %

AUC0–?b

(lg h/ml)

35 2240 34 2180 102.76 84.41 125.11 52.05

AUC0–1032

(lg h/ml)

35 1940 34 1900 102.01 86.84 119.83 41.72

Cmax (lg/ml) 35 4.05 34 3.73 108.47 97.86 120.22 26.03

AI autoinjector, AUC0–? area under the plasma concentration–time curve from 0 extrapolated to infinity, AUC0–1032 areaunder the plasma concentration–time curve from 0 to 1032 h post-dose, BMI body mass index, CI confidence interval, Cmax

maximum plasma concentration, gCV geometric coefficient of variation, gMean geometric mean, PFS prefilled syringe, PKpharmacokineticsa Adjusted for treatment and BMI group as fixed effectsb Based on observed last concentration values

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Fig. 4 BMI vs. total exposure by method of administra-tion (AI or PFS) (shown as log-transformed AUC0–?,

observed and Cmax) in a, b VOLTAIRE�-AI and c,d VOLTAIRE�-TAI. AI autoinjector, AUC0–?, observed

area under the plasma concentration–time curve from 0

extrapolated to infinity, based on observed concentrationsat the last observation, BMI body mass index, Cmax

maximum plasma concentration, Ln natural logarithm,PFS prefilled syringe

414 Rheumatol Ther (2018) 5:403–421

category in VOLTAIRE�-TAI. Increasing thick-ness of abdominal subcutis reduces the chanceof injections into the muscle, particularly if thefree needle is[ 4–5 mm [13]. As such, the tissueinto which a drug is injected, and therefore PK,can be influenced by the amount of SC fat.

There may also be a gender effect, since thedistribution of fat and muscle tissue differsbetween men and women.

Overall, the relationship between BMI/bodyweight and the PK of BI 695501 was similarregardless of presentation. However, differences

Fig. 4 continued

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in the gMeans were observed when brokendown by BMI group; in the low BMI group,gMeans were higher with PFS presentation thanwith AI presentation. This finding was reversedin the high BMI group. One reason for thisobservation may be that the PFS group tendedto have more subjects at the lower end of thelow BMI category, while the AI group had moresubjects at the higher end of the low BMI group.The low sample size likely also contributes tothis finding.

There is a clear relationship between bodyweight and systemic exposure to adalimumab,which is expected to be due to a difference involume of distribution based on body weightrather than BMI, since Immunoglobulin G (IgG)is hydrophilic, and distributed equally inplasma and extracellular fluid in peripheral tis-sue (with relatively permeable endothelium).

In common with previous findings for thereference product [1], BI 695501 exposure wasinversely related to BMI (VOLTAIRE�-AI) andbody weight (VOLTAIRE�-TAI). This expectedcorrelation has also been observed with otherbiologics [14]. Importantly, this relationshipwas independent of method of administration(i.e., AI or PFS), as seen by the considerableoverlap in individual exposure values over thefull BMI/body weight range following AI andPFS administration.

AEs observed during the study were primarilyISRs. Reactions of this type are common foranti-TNFa drugs [15] and are usually mild and

resolve rapidly. The numerically greater pro-portion of ISRs in the AI group compared withthe PFS group in the VOLTAIRE�-AI study maybe explained by a relatively higher pressureapplied with the AI against the skin; users mayhave pressed the AI firmly against the skinduring injection, versus a more cautiousadministration with a PFS. Additionally, the AIhas a standardized 3-s injection time whereasthere is more variability possible with the PFS;subjects could slow down the injection speed inPFS if they found it painful, potentially leadingto fewer ISRs. Patients have reported less painwith AI over PFS in other studies [6, 16], whichappears to be at odds with the increased ISRsseen in the VOLTAIRE�-AI study.

With regard to immunogenicity, in bothstudies, ADAs were evident in approximatelyhalf to three-quarters of subjects in each group.A direct comparison of BI 695501 administeredvia AI or PFS did not show any relevant differ-ence in terms of ADA frequency, titers, and thefrequency of nAbs, thereby demonstrating noeffect of the presentation on immunogenicity.

Taken together, the data derived from thesestudies demonstrate that the PK of BI 695501 isindependent of presentation, and therefore thetherapeutic efficacy would remain the same.This is in line with recent data on the anti-TNFaagent, golimumab, for which no differenceswere found for PK parameters between AI andstandard needle and syringe administration[17].

Table 6 Overview of adverse events

VOLTAIRE�-AI VOLTAIRE�-TAI

BI 695501 AI(N = 35)

BI 695501 PFS(N = 36)

BI 695501 AI(N = 81)

BI 695501 PFS(N = 81)

Number of subjects [n (%)] with:

C 1 AE 29 (82.9) 29 (80.6) 61 (75.3) 58 (71.6)

C 1 AE related to trial

drug

20 (57.1) 16 (44.4) 31 (38.3) 30 (37.0)

C 1 serious AE 0 0 2 (2.5) 1 (1.2)

Deaths 0 0 0 0

AE treatment-emergent adverse event, AI autoinjector, PFS prefilled syringe

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Table 7 Summary of adverse events by system organ class and preferred term occurring with an incidence[ 5% in anygroup

System organ classPreferred term

VOLTAIRE�-AI VOLTAIRE�-TAI

AI (N = 35)n (%)

PFS (N = 36)n (%)

AI (N = 81)n (%)

PFS (N = 81)n (%)

C1 AEa 29 (82.9) 29 (80.6) 29 (82.9) 58 (71.6)

General disorders and administration-site conditions 20 (57.1) 17 (47.2) 30 (37.0) 28 (34.6)

Injection-site erythema 18 (51.4) 13 (36.1) 14 (17.3) 7 (8.6)

Injection-site swelling 7 (20.0) 3 (8.3) 6 (7.4) 5 (6.2)

Injection-site induration 4 (11.4) 1 (2.8) 4 (4.9) 5 (6.2)

Injection-site pain 3 (8.6) 0 5 (6.2) 4 (4.9)

Injection-site pruritus 1 (2.9) 2 (5.6) 4 (4.9) 2 (2.5)

Fatigue 0 2 (5.6) 0 3 (3.7)

Influenza-like illness 0 2 (5.6) 5 (6.2) 5 (6.2)

Infections and infestations 8 (22.9) 4 (11.1) 20 (24.7) 17 (21.0)

Nasopharyngitis 8 (22.9) 2 (5.6) 11 (13.6) 9 (11.1)

Nervous system disorders 5 (14.3) 8 (22.2) 19 (23.5) 12 (14.8)

Headache 4 (11.4) 6 (16.7) 16 (19.8) 11 (13.6)

Paraesthesia 2 (5.7) 1 (2.8)

Musculoskeletal and connective tissue disorders 7 (20.0) 3 (8.3) 9 (11.1) 15 (18.5)

Back pain 3 (8.6) 1 (2.8) 5 (6.2) 8 (9.9)

Neck pain 2 (5.7) 1 (2.8) 1 (1.2) 1 (1.2)

Pain in extremity 2 (5.7) 0 1 (1.2) 0

Injury, poisoning, and procedural complications 4 (11.4) 0 4 (4.9) 3 (3.7)

Contusion 3 (8.6) 0 2 (2.5) 1 (1.2)

Respiratory, thoracic, and mediastinal disorders 2 (5.7) 1 (2.8) 9 (11.1) 12 (14.8)

Oropharyngeal pain 2 (5.7) 0 2 (2.5) 9 (11.1)

Gastrointestinal disorders 1 (2.9) 4 (11.1) 18 (22.2) 23 (28.4)

Abdominal discomfort 0 1 (2.8) 8 (9.9) 9 (11.1)

Nausea 0 1 (2.8) 8 (9.9) 4 (4.9)

AE treatment-emergent adverse event, AI autoinjector, PFS prefilled syringea Treatment-emergent AEs are defined as AEs that started or worsened in intensity on or after the first and single dose oftrial medication up to 10 weeks (70 days) post-dose

Rheumatol Ther (2018) 5:403–421 417

AIs are a popular means for self-administer-ing SC agents. Their use may be particularlyhelpful for patients with limited manual dex-terity, for example, with RA, psoriatic arthritis,or severe palmar psoriasis [18]. The availabilityof BI 695501 as both PFS and AI is expected togive options to patients with different prefer-ences or abilities.

Limitations

These healthy subjects did not have limitedfunction of the hand; therefore, the relativehandling characteristics of the two presenta-tions in patients with impaired dexterityremains uncertain. However, data from theVOLTAIRE�-RL study of AI use in patients with

active RA has shown that patients are able tohandle the AI without difficulty [19]. The open-label nature of the study has the potential tointroduce bias into the reporting of the safetydata.

CONCLUSIONS

Administration of BI 695501 with either an AIor PFS demonstrated similar PK and comparableimmunogenicity. No specific safety concernswere raised with either presentation. Compara-bility of PK between presentations was main-tained across the broad range of BMIs and bodyweights, indicating that AI and PFS can be usedindependently of those factors and administra-tion location.

Fig. 5 Proportions of patients who were iADA-positive and ii nAb-positive in aVOLTAIRE�-AI and bVOLTAIRE�-TAI.ADA anti-drug antibody, AI autoinjector, nAb neutralizing antibody, PFS prefilled syringe

418 Rheumatol Ther (2018) 5:403–421

ACKNOWLEDGEMENTS

Funding. These studies and this publicationwere supported by Boehringer Ingelheim Inter-national GmbH, Ingelheim am Rhein, Ger-many. All authors had full access to all of thedata in this study and take complete

responsibility for the integrity of the data andaccuracy of the data analysis.

Medical Writing, Editorial, and OtherAssistance. The authors wish to thank NualaPeter (Boehringer Ingelheim, Biberach, Ger-many) for her critical review of the manuscript.Medical writing assistance, supported

Fig. 6 ADA titers for ADA-positive subjects over time ina VOLTAIRE�-AI and b VOLTAIRE�-TAI. Box andwhisker plots indicating the median (line) within the 25%and 75% percentile box, arithmetic mean (diamond) and

outliers (circles), and 10% and 90% percentile for whiskers.ADA anti-drug antibody, AI autoinjector, nAb neutralizingantibody, PFS prefilled syringe

Rheumatol Ther (2018) 5:403–421 419

financially by Boehringer Ingelheim, was pro-vided by Liam Sebag Montefiore of Water-meadow, and Christina Jennings of GeoMed,Ashfield companies, part of UDG Healthcareplc. The authors wish to thank the participantsof the study.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Steven Ramael is an employeeof SGS and has received consultancy fees fromSGS. Benjamin Van Hoorick is an employee ofSGS. Renger Tiessen is an employee of PRA.Thijs van Iersel is an employee of PRA. ViktoriaMoschetti is an employee of Boehringer Ingel-heim. Benjamin Lang is an employee of Boeh-ringer Ingelheim. Sabrina Wiebe is an employeeof Boehringer Ingelheim. Bernd Liedert is anemployee of Boehringer Ingelheim. GirishJayadeva is an employee of Boehringer Ingel-heim. Ivo Sonderegger was an employee ofBoehringer Ingelheim at the time of the studyand is now an employee of Takeda Pharmaceu-ticals International AG, Zurich.

Compliance with Ethics Guidelines. Allprocedures performed in studies involvinghuman participants were in accordance withthe ethical standards of the institutional and/ornational research committee and with the 1964Helsinki Declaration and its later amendmentsor comparable ethical standards. Informedconsent was obtained from all individual par-ticipants included in the study.

Data Availability. All data generated oranalyzed during this study are summarized inthis published article/as supplementary infor-mation files.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any

noncommercial use, distribution, and repro-duction in any medium, provided you giveappropriate credit to the original author(s) andthe source, provide a link to the CreativeCommons license, and indicate if changes weremade.

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